Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease in this country affecting 500,000 people and costing in excess of $200 million per year for the treatment of end stage renal disease alone. Thus, it is important to expand our understanding of this disease. Our large and well-studied ADPKD population which includes 314 families with 521 ADPKD adults and 100 ADPKD children is ideal to accomplish this goal. The general hypothesis which has guided this project since its inception is that ADPKD is a systemic disorder due to gene defects which directly or indirectly result in an array of structural and functional disorders in multiple organs. From this hypothesis the project examines the clinical and genetic aspects of ADPKD and their interrelationship. Integrated with the genetic section, the clinical section examines the relationship between phenotypic and genotypic variability within and between families. A prime focus of this project is a better understanding of ADPKD in children in part by identifying phenotypic prognostic factors and by determining the effect of antihypertensive therapy on structural progression of the disease in children. We will extend our study of the natural history of intracranial aneurysms and examine the genotype of individuals and families with this manifestation. Another major focus of this project continues to be the elucidation of the mechanisms and effect of hypertension. Since left ventricular hypertrophy (LVH) is common both in hypertensive and normotensive ADPKD patients we will examine the role of the angiotensin converting enzyme DD genotype and the angiotensinogen gene variant M235T in the cardiovascular manifestations. We will complete the longitudinal study defining the optimal blood pressure for reversing LVH and for retarding the development of renal insufficiency. The last major focus of this project is to utilize the breakthroughs in ADPKD genetics to critically examine the genetic basis for the phenotypic variation. We will identify and characterize athe mutations in the ADPKD1 gene. We will examine relationship between genetic variability at he ADPKD2 and ARPKD loci and sibling pair phenotypic variability. Thus this study will significantly add to our fund of knowledge of this important disease.